JPH02191274A - Dihydroindole derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I and salt of said compound [R<1> is H or lower alkyl; R<2> is lower alkyl; R<3> is formula II (R<4> is lower alkyl; R<5> is H or imino-protecting group; A<1> is lower alkenylene), group expressed by the formula -A<2>-R<6> (R<6> is azabicyclo 5-12C alkyl may be substituted with lower alkyl) or azabicyclo 5-12C alkylidene alkyl may be substituted with lower alkyl]. EXAMPLE:2,3-dihydro-3,3-dimethyl-1-[(E)-3-(5-methyl-1-trityl-1Himidazo l-4-yl)-2- propenoyl) indole. USE:Curing agent for insanity, headache, neuralgia or gastrointestinal injury, etc. PREPARATION:A compound expressed by formula III is reacted with a compound expressed by the formula HOOC-R<3> to afford the compound expressed by formula I.

Description

Detailed Description of the Invention Field of Ea Industrial Application] This invention relates to a novel dihydroindole derivative, and more specifically, 5-hydroxytryptamine (5-H
T) The present invention relates to novel dihydroindole derivatives having pharmacological activities such as antagonistic effects, pharmaceutically acceptable salts thereof, and methods for producing them.

OBJECT OF THE INVENTION 1 An object of the present invention is to provide novel dihydroindole derivatives and pharmaceutically acceptable salts thereof useful as potent selective antagonists of 5-HT receptors.

More specifically, psychosis (e.g. schizophrenia, Wkvi, etc.), central nervous system (CNS) disorders such as anxiety and depression, headaches (e.g. migraine, cluster headache, vascular headache, etc.) and neuralgia in humans and animals. (e.g., trigeminal neuralgia, etc.), gastrointestinal dysfunction symptoms such as indigestion, peptic ulcers, reflux esophagitis, and flatulence, gastrointestinal disorders such as irritable bowel syndrome (IBS), and cancer treatment. To provide a dihydroindole derivative and a pharmaceutically acceptable salt thereof that can be used as an active ingredient of a 5-117 antagonist useful for the treatment or prevention of nausea and vomiting, motion sickness, etc. It is in.

Another object of this invention is to provide a method for producing such dihydroindole compounds and pharmaceutically acceptable salts thereof.

[Prior Art] In this technical analysis, for example, the following compounds are known.

[Structure of the Invention] As a result of intensive research, the inventor of the present invention succeeded in obtaining a dihydroindole derivative having strong pharmacological activity and a pharmaceutically acceptable salt thereof.

The dihydroindole derivative of this invention is novel and can be represented by the following formula (1).

Co-R” [wherein R1 is hydrogen or a lower alkyl group, R1 is a lower alkyl group (wherein, R4 is a lower alkyl group, R11 is hydrogen or an imino protecting group, and A1 is a lower alkenylene group)] A group represented by the formula % formula % [wherein R6 is an azabicyclo(Ca -C+z)alkyl group which may be substituted with a lower alkyl group, and A2 means a lower alkylene group or a lower alkenylene group] , or an azabicyclo(Cs-C+2) alkylidene (lower) alkyl group which may be substituted with a lower alkyl group] The inventor of the present invention also proposed a method for producing a dihydroindole derivative represented by the above formula (1). We have succeeded in providing the following two methods.

Process 1 Process 2 (It) (Ia) Co-R3 or a pharmaceutically acceptable salt thereof (Ib) or a pharmaceutically acceptable salt thereof [However, in the above formula, R', Rn3, R4Al
have the same meanings as before; R6 means an imino protecting group] and [Detailed Description of the Invention] The object of this invention is represented by the above formula (1), (!), or (ib). The chemical structure of the dihydroindole conductor has one or more asymmetric carbon atoms and 2-type packing in the molecule, so that one or more optical isomers or geometric isomers may exist. Therefore, these isomers or mixtures thereof are also included within the technical scope of the present invention.

In particular, the group represented by the symbol R6 in the dihydroindole derivative (1) formula, (Ia) formula or (Ib) formula is "azabicyclo (Cs
-Co2) alkyl group, the dihydroindole derivatives (1), (I a), and (I b) can have two steric configurations: an endo configuration and an exo configuration. Therefore, although these cases are also included within the technical scope of the present invention, the end arrangement is more preferred.

Preferred salts of the compounds represented by formulas (1), (Ia) and (1b) are non-toxic and pharmaceutically acceptable general-purpose salts, such as hydrochloride, hydrobromide, sulfuric acid salt, etc. salts, salts with inorganic acids such as phosphates; for example, formates, acetates, trifluoroacetates, maleates, tartrates,
Salts with organic carboxylic acids or sulfonic acids such as methanesulfonate, benzenesulfonate, P-toluenesulfonate; basic or acidic salts such as salts with arginine, salts with aspartic acid, salts with glutamic acid, etc. Preferred examples include acid salts such as salts with amino acids; and the like.

With regard to each of the above and below definitions in this specification, examples that fall within the technical scope of the present invention are as follows.

The term "lower" means, unless otherwise specified, a carbon number of 1 to 6, preferably a carbon number of 1 to 4.

Suitable "lower alkyl groups" include linear or branched groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, pentyl, hexyl, etc. . The most preferred among these is methyl.

Suitable "lower alkylene groups" include those having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, propylene, tetramethylene, methyltrimethylene, dimethylethylene, hexamethylene, and the like. Among these, methylene or ethylene is most preferred.

Suitable "lower alkenylene groups" include, for example, vinylene, propenylene, etc., and among these, Cx-C4 alkenylene is preferred, and vinylene is most preferred.

Suitable “azabicyclo(Cs-C,*)alkyl group”
Examples include azabicyclo[3,2,1]octyl, azabicyclo[2,2,2]octyl, azabicyclo[3,3,1]nonyl, etc., and these include the above-mentioned lower alkyl groups (for example, methyl, ethyl etc.), and even more preferably, azabicyclo (Cy-
Cto) alkyl, more preferably azabicyclo<c
m-Co) alkyl, most preferably 8
-methyl-8-azabicyclo[3,2,1]octyl,
1-azabicyclo[C2,1]octyl, 9-methyl-
9-azabicyclo[3,3,1]nonyl.

Suitable “azabicyclo(Cs-C+2)alkylidene(
Examples of "lower) alkyl groups" include azabicyclo[]
, 2.1] azabicyclo[3,
azabicyclo[2,2,1]octylidene(lower)alkyl, azabicyclo[2,C2]octylidenemethyl, etc.
, 2,2] octylidene (lower) alkyl, etc., which may be substituted with the above-mentioned lower alkyl group (for example, methyl, ethyl, etc.), and still more preferred is azabicyclo (C? -C0°) Alkylidene(lower)alkyl, more preferably azabicyclo(Ca-Co
) alkylidene(lower)alkyl, most preferably (8-methyl-8-azabicyclo(3,2,13
octylidene) methyl, (1-azabicyclo[2,2,
2] octylidene) methyl.

Suitable "imino protecting groups" include general purpose imino protecting groups,
Preferred examples include benzyl, benzhydryl,
Mono (or di, or tri) phenyl (such as trityl)
(lower) alkyl such as lower) alkyl;
The most preferred among these is trityl.

Dihydroindole visiting conductor [
Process 1.2 for manufacturing [which may be represented by formula (1) below], including the cases shown by (1), (Ia), and (!b), will be described in detail below.

Process 1 The target substance (I) of this invention or a salt thereof is a compound (l
It can be produced by reacting compound (III) or a reactive derivative thereof at an imino group or a salt thereof with compound (III) or a reactive derivative at its carboxy group or a salt thereof.

Suitable reactive derivatives of the imino group of the compound (■) include compounds formed by reacting silyl compounds such as bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide, bis(trimethylsilyl)urea, etc. with the compound (■ri). In addition to the silyl conductor,
For example, derivatives obtained by reacting phosphorus trichloride, phosgene, etc. with a compound (I) are included.

Suitable reactive derivatives of the carboxy group of compound (III) include, for example, acid halides, acid anhydrides, activated amides, activated esters, and the like. Preferred examples of the above-mentioned reactive derivatives include acid chloride; acid azide;
For example, substituted phosphoric acids [e.g., dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, etc.], dialkyl phosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid [e.g., methanesulfonic acid, etc.], aliphatic carboxylic acid [e.g. Acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, valeric acid, isovaleric acid, 2-ethylbutyric acid, trichloroacetic acid, etc.], or aromatic carboxylic acids [benzoic acid, etc.]
Mixed acid anhydrides with acids such as; symmetrical acid anhydrides; activated amides with imidazole, 4-fltJll imidazole, dimethylpyrazole, triazole or tetrazole, etc.; or active esters [e.g. cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(
CH3)2 N”・OH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthio ester , p-nitrophenylthioester, p-talesylthioester, carboxymethylthioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolylthioester, etc.]: or N-hydroxy compound [e.g., N,N-dimethylhydroxylamine, 1 -hydroxy-2-(IH)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-IH-benzotriazole, etc.). It can be arbitrarily selected depending on the type of (Ill).

This reaction can be carried out using commonly used solvents such as water, alcohols [e.g. methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, etc.
It is generally carried out in N,N-dimethylformamide, pyridine, or any other organic solvent that does not adversely affect the progress of the reaction. These general-purpose solvents can also be used as a mixed solvent with water.

In this reaction, when compound (III) is used in the form of free acid or its salt, a commonly used condensing agent such as N,N'-dicyclohexylcarbodiimide; N-cyclohexyl-No. -morpholinoethylcarbodiimide diN-cyclohexyl-N'-(4-
diethylaminocyclohexyl)carbodiimide, N
, N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide: N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;N,N'-carbonylbis-(2-methylimidazole): pentamethylene ketene -N-cyclohexylimine; diphenylketene-N-cyclohexylimine: ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; methyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride ; diphenylphosphoric azide: thionyl chloride, oxalyl chloride; lower alkyl haloformate [e.g. ethyl chloroformate, chlor! ! isopropyl acid, etc.]; triphenylphosphine; 2-ethyl-twohydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intermolecular salt; 1-(p-chlorobenzenesulfonyloxy )-6-chloro-IH-benzotriazole,
It is desirable to carry out the reaction in the presence of a so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, or the like.

This reaction can also be carried out in the presence of an inorganic or organic base, such as an alkali metal bicarbonate, a tri(lower)alkylane, pyridine, N-(lower)alkylmorphosine, N,N-di(lower)alkylbenzylamine, etc. You can also do it below.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating.

Compound (III) used in this process is produced according to a conventional method.

Process 2 The target substance (I b) of this invention or a salt thereof can be produced by subjecting compound (Ia) or a salt thereof to an elimination reaction of the imino protecting group.

Suitable reactions include conventional means such as hydrolysis, reduction, and the like.

Hydrolysis is preferably carried out in the presence of a base or an acid.

Suitable bases include, for example, alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxides (e.g., magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonates (e.g., carbonic acid, etc.). sodium, potassium carbonate, etc.), alkaline earth metal carbonates (
(e.g. magnesium carbonate, calcium carbonate, etc.), alkali metal hydrogen carbonates (e.g. sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal acetates (e.g. sodium acetate, potassium acetate, etc.), alkaline earth metal phosphates (
(e.g., magnesium phosphate, calcium phosphate, etc.), alkali metal hydrogen phosphate salts (e.g., disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.), and inorganic bases such as trialkylamines (e.g., trimethylamine, triethylamine, etc.), picoline, N -Methylpyrrolidine, N-
Methylmorpholine, 1,5-diazabicyclo[4,3,
0] non-5-one, 1,4-diazabicyclo[2,2
, 2] Octane, 1. S-diazabicyclo[5,4,0
] Examples include organic bases such as Undecii 5 and the like.

Hydrolysis using a base is often carried out in water, a hydrophilic solvent, or a mixed solvent thereof.

Suitable acids used for hydrolysis include, for example, formic acid,
Examples include organic acids such as acetic acid and propionic acid, and inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid.

Hydrolysis using an acid is usually carried out in an organic acid, water, or a mixed solvent thereof.

The reaction temperature is not particularly limited, and is usually carried out at room temperature or under heating.

The reduction reaction includes catalytic reduction and chemical reduction, and in both cases, it is carried out according to conventional methods.

The method applied to this elimination reaction can be arbitrarily selected depending on the type of imino protecting group.

The object substance (I) of the present invention can be isolated and purified according to conventional methods, for example, extraction, precipitation, fractional crystallization, recrystallization, chromatography, and other methods can be used.

The target substance (1) thus obtained can be converted into its salt by a conventional method.

The object compound (1) of the present invention is novel and has pharmacological activities such as 5-HT antagonistic activity, especially 5-HTs antagonistic activity, and therefore is effective against psychosis (e.g., schizophrenia, phthisis, etc.), anxiety, and depression. central nervous system (CNS) disorders, pains such as headaches (e.g. hemigraine, cluster headache, vascular headache, etc.) and neuralgia (e.g. trigeminal neuralgia, etc.), indigestion, peptic ulcers, reflux esophagitis and flatulence, etc. It is useful for treating or preventing gastrointestinal disorders such as symptoms of gastrointestinal dysfunction and irritable bowel syndrome (185) associated with cancer treatment, nausea or vomiting associated with cancer treatment, and motion sickness.

Furthermore, the object compound (I) of the present invention can be used to treat and/or prevent obesity, pulmonary embolism, arrhythmia, withdrawal symptoms resulting from addiction to abused drugs or substances, stress-induced mental disorders, rhinitis, and serotonin-induced nasal disorders. It is considered to be useful for

In order to clarify the usefulness of target substance (1), representative compounds of the present invention are selected and their pharmacological activities are as follows.

Bezold-Jaris
A male Sublargo-Dawley rat weighing 1260-350 g was anesthetized intraperitoneally with 1.26 g/kg of urethane.

Blood pressure and heart rate were continuously monitored in the left common carotid artery using a pressure transducer. The right major leg vein was intubated and drugs were administered intravenously (lv). The patient's trachea was also intubated to make breathing easier.

2-methyl-5-hydroxytryptamine (3
A control bradycardia response was set up with a bolus injection of 2 μs/kg, lv). - Once the heart rate has returned to basal values, the rat is administered the test compound IV) and then administered with 2-methyl-5-hydroxytryptamine for 32 μs after a 5-minute interval.
/kg, lv) was given as a bolus.

2.3-dihydro-3,3-dimethyl-1-((8-methyl-8-azabicyclo[3,2,13oct-3-yl)acetylcoindol] of this invention When using the target compound (1) for therapeutic purposes, organic or inorganic solid or liquid excipients for oral, parenteral and topical administration may be used.
It is used in the form of conventional pharmaceutical preparations containing the compound as an active ingredient in admixture with a pharmaceutically acceptable carrier.

Pharmaceutical formulations may be in solid form such as tablets, granules, powders, capsules, or liquid forms such as solutions, suspensions, syrups, emulsions, lemonades, and the like.

If necessary, auxiliaries, stabilizers, wetting agents, and others such as lactose, citric acid, tartaric acid, stearic acid, maglucicum stearate, terra alba, sucrose, cornstarch, talc, gelatin, agar, pectin, and peanuts are added to the above formulation. Commonly used additives such as oil, olive oil, cocoa butter, ethylene glycol, etc. may be included.

The dosage of compound (1) varies depending on the patient's age, condition, type and condition of disease, type of compound (1) used, etc. Generally, the compound (1) of the present invention may be administered to a patient in an amount between 0.01 mg and about 500 doses per day, or more.
05mg, 0.25mg.

0.5g% 1mg, 10i+g, 20
Otorig, SOs+g, 1001g may be administered.

The present invention will be explained in more detail below with reference to production examples and examples.

Sodium hydride (60% mineral oil solution) was added to a solution of dimethylphosphonoacetic acid methyl ester (0.22 g) in tetrahydrofuran (50%) at 5°C.

This was stirred at 5°C for 20 minutes, and then 5-methyl-1
-Trityl-IH-I-Dacyl-4-carbaldehyde (0.35g) was added. The resulting mixture was stirred at high temperature in a nitrogen atmosphere for 16 hours.

After diluting with water, the reaction mixture was extracted three times with methylene chloride. Combine the organic solvent layers, add sodium hydrogen carbonate aqueous solution,
After washing with water and brine in that order, it was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained oil was purified by column chromatography packed with silica gel (0
, 5% methanol-methylene chloride).
Oily (E)-3-(5-methyl-1-trityl-IH
-imidazol-4-yl)-2-propenoic acid methyl ester (0,329 g) was obtained.

IR (NuJol): 1705.1630.12
1tOcm-'NMR (CDCIs, δ: 1.53
(31+, s), 3.70 (3H, s), 6.53
(111, d, J-15Hx), 7.00-7.50 (
16H, m), 7.50 (IH.

d, J-15Hz) 11■Methanol-dioxane mixed solution of E)-3-(5-methyl-1-trityl-IH-imidazol-4-yl)-2-propenoic acid methyl ester (0,315 g) (
1: IN sodium hydroxide aqueous solution (1
, 8 ml) was added and the resulting mixture was stirred at room temperature for 19 hours. After the solvent was distilled off, the residue was diluted with cold water, neutralized by adding an aqueous oxalic acid solution, and extracted three times with methylene chloride. The organic solvent layers were combined, washed with water and brine, and then dried over anhydrous magnesium sulfate. When the solvent was distilled off under reduced pressure, a crystalline residue was obtained, which was recrystallized from a chloroform-hexane mixture to obtain (E)-3-(5-methyl-1-trityl-IH-imidazol-4-yl).
-2-propenoic acid (2521 g) was obtained.

mp: 197-201'e IR (NuJol): 2200-2800.168
5.1635.1275 cm-'NMR(DMSO-
da, δn: 1.50 (3H, s), 6.2
7 (IH, d.

J-15Hz), 6.90-7.60 (17H, l),
12.00 (IH, s) 9-methyl-9-azabicyclo[3,3,1]nonane-
A 60% sodium hydride dispersion (5.13 g) was added to a solution of 3-one (111.74 g) and ethyl diethylphosphonoacetate (18.74 g) in dry benzene (20011) at room temperature over 10 minutes. The reaction mixture was stirred at the same temperature for 30 minutes and then for 40 hours under reflux, and then added to water (50 ml).
and ethyl acetate (100ffll). After separating the organic solvent layer and washing with water (50 ml), IN
Extracted twice with hydrochloric acid (30 ml x 2). 20% in extract
After adjusting the pH to 9 by adding an aqueous sodium hydroxide solution,
Extracted with ethyl acetate three times (50 ml x 3). The extract was dried over anhydrous magnesium sulfate, concentrated, and the residue was purified by column chromatography packed with silica gel (1 kg) (eluted with 5% methanol-chloroform). Fractions containing the target substance were collected and concentrated. , 9-methyl-9-azabicyclo[3,3,1]non-3-ylidene acetic acid ethyl ester (11,1 Hg) was obtained.

111 (NuJol): 1730.1560.1
250 cm-”NMR (CDCIs, δ): 1
．． 27 (3H, t, J-7, 1511z), 1.3-
1.9 (7H, m), 2.73 (3N, s), 2.
3-2.4(ill, s).

2.9-3.2 (4H, s), 4.15 (2H, J
=7.511ri, 5.49(to, a, J-4, a
7oz) Mass II/! -223 9-methyl-9-azabicyclo[3,3,1]non-3
-ylidene acetic acid ethyl ester (9.4 g) and platinum hydroxide (Adams catalyst) (750+++ g) were combined with acetic acid (120 g).
11) plus contact exposure for 17 hours under a pressure of 60 psi. The catalyst was filtered off, and the solvent was distilled off from the filtrate under reduced pressure.

The residual oil was dissolved in chloroform (10011) and neutralized by adding aqueous sodium bicarbonate solution. The organic solvent layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 9-methyl-9-azabicyclo[3,3,1]non-3-yl acetic acid ethyl ester (9 , 45 g) was obtained.

In(film): 2850.1725.1430
cm-'NMR (CDCIs, δ): 0.9
-2.4 (13H, ■), 1.27 (311, t.

J-7,37Hx), 2.51(3H,s), 2.
9-3.2 (21(, m).

4.12 (2H, q, J-7, 37Hz) Direction■1 9-Methyl-9-azabicyclo[3,3,1]non-3
-ylacetic acid ethyl ester (740 mg), IN aqueous sodium hydroxide solution (51 ml) and ethanol (3
, 6 mL) was stirred at room temperature for 5 hours.

The reaction mixture was neutralized by adding IN hydrochloric acid (5.1 ml), and then the solvent was evaporated and the residue was dissolved in chloroform (30 ml).
After diluting with fat l) and drying with anhydrous magnesium sulfate,
When the solvent was distilled off under reduced pressure, 9-methyl-9-azabicyclo[3,3,13non-3-yl acetic acid (544a+g) was obtained.

In(NuJol): 3250.1570.14
50 cm-”NMn (COCl, δ): 1.
2-3.1 (13B, +*), 2.84 (31+, s
).

3.50 (28,d, J-10,4Hz), 11.95
(III, br s) Mass: m/z-197
(M”) Futo ■ Yu (E)-3-(5-methyl-1-trityl-IH-imidazol-4-yl)-2-propenoic acid (2.0 g)
, 1-hydroxybenzotriazole (0,686g)
and 1-ethyl-3-(3-diethylaminopropyl)carbodiimide hydrochloride (0.97 g) were added to N,N-dimethylformamide (10 liters) and the resulting mixture was stirred at room temperature for 1 hour and 40 minutes. Add 2. to the resulting solution.
3-dihydro-3,3-dimethylindole (0,75
g) and N,N-dimethylformamide After stirring for 0.5 hours, triethylamine (11) was added to the mixture and stirring was continued for 14 hours at room temperature. When the reaction mixture was diluted with water, a precipitate formed. This was collected, washed with water, and then dissolved in methylene chloride. The organic solvent layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by column chromatography packed with silica gel (eluted with a 1% methanol-methylene chloride mixture) and recrystallized from a toluene-hexane mixture to give 2.3-dihydro-3.3-dimethyl-
1-[(E)-3-(s-methyl-1-trityl-IH-imidazol-4-yl)-2-propenoyl)indole (2.35 g) was obtained.

Otori p: 2311-246℃ IR (NuJol): 1B50, 1605,
1590. 1280 cm-”NMR (DMSO-
da, δ): 1.30 (6H, s), 1.5
3(3)1,s).

3,96(2)1,s), 6.80-7.50(2
2H. m) Trap group ■U2,3-dihydro-3,3-dimethyl-1-[(E)-
3-(5-Methyl-1-trityl-IH-imidazol-4-yl)-2-propenoyl]indo-/I/
(1.03g) (F) Water-acetic acid (1-: 3,
The solution was stirred at 65°C for 1.5 hours. The solvent was distilled off to give a crystalline residue, which was diluted with water, neutralized with an aqueous sodium bicarbonate solution, and extracted three times with methylene chloride. The organic solvent layers were combined, washed successively with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by column chromatography packed with silica gel (eluted with a 5% methanol-methylene chloride mixture), and the resulting oil (0.57 g) was dissolved in hot methanol, and maleic acid (235 mg) was added. When the crystalline substance obtained by distilling off the solvent is recrystallized from methanol, 2,3-dihydro-3,3-dimethyl-1-
[(E)-3-(5-methyl-IH-imidazole-4
-yl)-2-propenoylcoindole maleate (0.5 g) was obtained.

Eaves: 198-201 t: IR (NuJol): 1670, 1830.
1fiOO, 1570. 1280cm-'NMR
(DMSO-da, δ) 1.33 (6N, s),
2.37 (311.S).

3, 97 (2H, s), 6.10 (2H, s), 6
．． 93(1)1, d.

J-15Hz), 7.00-7.30 (3H, m)
, 7.50 (IH, d.

J=1511x), 8.10 (IH, d, J=7Hz)
, 8.53 (IH.s).

13,40 (3H, br s) N,N-dimethylformamide (10 l) of (8-methyl-8-azabicyclo[3.2.1]oct-3-yl)acetic acid (0.50 g) ) solution contains 1-hydroxy-I
H-benzotriazole (0.44 g') and dicycloxylcarbodiimide (0.118 g) were added, and the resulting mixture was stirred at room temperature for 1 hour. Add 2.
3-dihydro-3,3-dimethylindole (0.47
g) was added and stirred at room temperature for 1 day. The reaction solution was diluted with water (10
(Ml) and the precipitate was filtered off. The filtrate was washed with ethyl acetate and extracted with chloroform (adjusted to pH-13 using an aqueous sodium hydroxide solution). The extract was dried over magnesium sulfate, the solvent was distilled off, and water (3
0 ml) and rubbed on the wall, 1-[(8-methyl-8-azabicyclo[3,2,1]oct-3-yl)
A crude product of [acetyl]-2,3-dihydro-3,3-dimethylindole was obtained, which was mixed with an ethanol-water mixture (
2: 8. When recrystallized with v/v), the purified product (0,5
8g) was obtained.

mpo: 80-83℃ IR (NuJol): 1640.1595 cm
-'NMR (CDCIs, δ): 1.33 (
6H, s), IJ-2, 8 (IIH, idiom).

2.28 (3H, s), 2.9-3.3 (2H, ■)
, 3.75 (2H, s).

6.8-7.3 (3H, m), 8.18 (IH, br
d, J-811x) Mass: m/z-312
(M'') 衷 41 The following compound was obtained in the same manner as in Example 3.

(1) 1-[(8-methyl-8-azabicyclo(3,2
,1]oct-3-ylidene)acetyl]-2,3-dihydro-3,3-dimethylindole IR (Neat)
: 1650.1590 cm-'NMR (CDC1
s, δ): 1.34 (6Hj), 1.3
−3.4 (IOH, Im).

2.38 (311, s), 3.711 (Hl, br
s), 5.86 (IH, br d.

JII5Hz), 6J-7,3(3H,s),
8.18(1)1. brd.

J-8Hz) When the above compound is treated with hydrochloric acid, t-((a-methyl-
8-azabicyclo[3,2,1]oct-3-ylidene)acetyl]-2,3-dihydro-3,3-dimethylindole hydrochloride was obtained.

Amount p: 5s-as °C IR (NuJol): 1B50.1635.15
90 cm-'NMn (DMSO-do, δ): 1
．． 30(6H,s), L, S-3,4(10)1. m
).

3.6-4.3 (2H, ■), 3.83 (3H, s)
, 5.70 (18, br s), 7.4-6.8 (
3H, m), Jl, 01 (IH, d.

J-7) 1x), 11.20 (IH, br s) Mas
s: s/x-310 (M” free) (2) 2
．． 3-dihydro-3-methyl-1-[(8-methyl-8
-Azabicyclo(3,2,1]oct-3yl)acetylcoindole Death: 7t 110℃ IR (NuJol): 1645.1593 cm
"NMR (CDCIs, δ): 1.0-2.9 (1
7H, @), 2.9-3.25 (2H, l), 3.3
-3.7 (2H, l), 4.0-4.4 (IH, @).

6.8-7.4 (3H, @), C20 (11 amount, d
, J-8Hz) Mass: s/z-298(M”
)(3) 2,3-dihydro-3,3-dimethyl-1-
[(1-Azabicyclo[2,2,2]oct-3-ylidene)acetylcoindole III (Naat): 1840.1615.159
0 cm-' When the above compound is treated with hydrochloric acid, 2.3-
Dihydro-3,3-dimethyl-1-[(1-azabicyclo(2,2,2]oct-3-ylidene)acetylcoindole hydrochloride was obtained.

Otori p: 287-269 ℃ 111 (NuJol): 16BG, 1620.1
590 cm-'NMR (DMSO-d, δ)
: 1.3G (6H, S), 1.7-2.3 (4H, a
), 2J-3, 11 (5) 1. Otori), 3.
9-4.7 (4H, m).

8.47 (IH, br s), 7.0-7.8 (4H,
s), 8.10 (IH, br s) Mass: gt/z-298 (M", tre
e) (4) 2,3-dihydro-3,3-dimethyl-1
-[(1-Azabicyclo[2,2,2]oct-3-yl)acetylcoindole tap: 201-204°C IR (NuJol): 1B45.1590 cm
-'NMR (CDCIs, δ): 1.33 (6H
, s), 1.5-4.0 (16tl).

6.9-7.3 (311, m), 8.13 (Ill
, d, J-7Hz) Mass: m/z-298 (M") 11 groups 1 (9-methyl-9-azabicyclo[3,3,1]non-
(3-yl)acetic acid (9s5mg) in chloroform (3ou
l) Add 10% hydrochloric acid-diethyl ether solution (v/w
) (2 ml) was added and stirred at room temperature for 10 minutes. The reaction mixture was evaporated to dryness under reduced pressure, and the residue was mixed with dry benzene (5 ml).
1) and thionyl chloride (2 1) were added, and the mixture was stirred at room temperature for 3 hours. After distilling off the solvent, methylene chloride (1
0 ml) was added. Add 2,3-dihydro-3 to this mixture.
, 3-dimethylindole (438g), triethylamine (1,5-dimethyl) and methylene chloride (10ml) were added at 5°C, stirred at the same temperature for 0.5 hours, and then stirred at room temperature for 3 hours. The reaction mixture was diluted with water, adjusted to pH 9 with potassium carbonate, and then extracted with chloroform.

The extract was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by column chromatography packed with silica gel (eluted with 20% methanol-chloroform) and then recrystallized from a mixture of ethyl acetate and diethyl ether to give 2,3-dihydro-3,3-dimethyl-1-[( 9-methyl-9-
Azabicyclo[3,3,1]non-3-yl)acetylcoindole (0.22 g) was obtained.

sap: 117-118℃ IR (NuJol): 35G0.3280.1fi55
．． 1590.1480 cta-'NMR(DMSO-
da, δ): 0.8-1.2 (411, +s),
1.29(61(,s), 1.2-1.4(IH,
m), 1.8-2.5 (8H, m).

2.45 (3H, s), 2.9-3.1 (2H, m)
, 3.86 (28,S).

6.9-7.3(31(,l), 8.06(2H,
d, J-7,8Hz) Mass: s/x-326
(&I”) Dong Chung ■1 (8-methyl-8-azabicyclo[3,2,1]oct-3-yl)acetic acid (1,26 g), 1-hydroxybenzotriazole hydrate (1,07 g) and Dicyclohexylcarbodiimide (1,44g) was added to N,N-dimethylformamide (15111) and the resulting mixture was stirred at room temperature for 1.5 hours.To this was added 3,3-diethyl-2,3dihydroindole (1 , 211g) of N
, N-dimethylformamide (5 ml) solution was added and the reaction mixture was stirred for a further 72 hours at room temperature, diluted with water,
After making it basic by adding 3N aqueous sodium hydroxide solution,
After extraction with chloroform three times, the organic solvent layer was washed with water and brine, and then insoluble materials were filtered off and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography packed with silica gel (0.61 g) (eluted with 20% methanol-chloroform).
As a result, an oily substance (0.61 g) was obtained. This oil was treated with a hot methanol solution of maleic acid (0.208 g) and the solvent was evaporated. The residue is crystallized by treatment with a mixture of isopropyl alcohol and diethyl ether to give 3,3-diethyl-2,3-dihydro-s
-[(8-Methyl-8-azabicyclo[3,2,1]oct-3-yl)acetylcoindole maleate salt (0,627 g) was obtained.

mp 160-162°C IR (NuJol): 2000-2400.1690.
1650.1605°1590 cm-' NMR (MSO-d,) δ: 0.71 (6
H, t, J-78Z), 1.55-1.130 (6
8, 嘗), 2.10-2.60 (78, l), 2.
68 (3B, s).

2.78(2)1. Peng), 3.81 (211,br
s), 3.86 (2H, s).

6.03(2)1. s), 6.99-7.20 (31
1, m), 8. Of! (IH, d, J-mat?, 5Hx)

Claims (3)

[Claims] (1) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 is hydrogen or a lower alkyl group, R^2 is a lower alkyl group, R^3 is a formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^4 is a lower alkyl group, R^5 is hydrogen or an imino protecting group, and A^1 is a lower alkenylene group.) A group represented by the formula -A^2R^6 (in the formula, R^6 is an azabicyclo(C_5-C_1_2) alkyl group which may be substituted with a lower alkyl group, A
^2 means a lower alkylene group or lower alkenylene group) or an azabicyclo(C_5-C_1_2) alkylidene (lower) alkyl group which may be substituted with a lower alkyl group] Dihydroindole derivatives or pharmaceutically acceptable salts thereof. (2) A dihydroindole compound or its imino group represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 and R^2 each have the same meaning as stated in claim (1)] or a salt thereof, a carboxylic acid compound represented by the formula HOOC-R^3 [wherein R^3 has the same meaning as described in claim (1)] or a reactive derivative thereof in the carboxy group Or by reacting their salts, dihydroindole derivatives represented by the formula ▲mathematical formula, chemical formula, table, etc.▼ (in the formula, R^1, R^2, R^3 each have the same meaning as before) or A method for producing a pharmaceutically acceptable salt thereof. (3) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1, R^2, R^4 and A^1 each have the same meaning as stated in claim (1), R^ 5_a means an imino protecting group] A dihydroindole compound or a salt thereof,
By subjecting it to the elimination reaction of the imino protecting group, we have the formula ▲mathematical formula, chemical formula, table, etc.▼ (wherein, R^1, R^2, R^4 and A^1 each have the same meaning as before). A method of producing the indicated dihydroindole derivatives or pharmaceutically acceptable salts thereof.